Synthesis of steroids



United States Patent Patented Feb. 20, 1962 3,022,296 SYNTHESIS OF STEROIDS Josef Fried and Josef E. Herz, New Brunswick, N.J.,

assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Original application Apr. 2, 1956, Ser. No. 575,344, now Patent No. 2,920,084, dated Jan. 5, 1960. Divided and this application May 20, 1959, Ser. No. 817,703 7 2 Claims. (Cl. 260--239.55)

This application is a division of our application, Serial No. 575,344, filed April 2, 156, now Patent No. 2,920,084, which in turn is a continuation-in-part of our parent applications, Serial No. 434,672, filed June 4, 1954, now Patent No. 2,763,671, and Serial No. 483,166, filed January 20, 1955.

This invention relates to the synthesis of valuable steroids; and has for its objects the provision of an advantageous process of preparing steroids of the pregnene (including pregnene, allopregnene, pregnadiene, and pregnatriene) series having a 21-aldo or acetalized aldo group, a 9a-halo group, and an llp-hydroxy or ll-keto group; and of certain new steroids useful in the preparation of said steroids.

The process of this invention essentially comprises: (a) converting a 21-all anesulfonyloxy-9 3,1lfi-epoxy steroid of the pregnane series to the corresponding 21-bromo or chloro derivative thereof: (b) converting said 21-bromo or chloro derivative to the corresponding ZI-quaternary ammonium salt; (0) converting said 21-quaternary ammonium salt to the corresponding 21-nitrone derivative; and (d) converting the 21-nitrone to the corresponding ZI-aldehyde or 21-acetal derivative.

The new compounds of this invention comprise: (A) 21-bromo or chloro-913, llp-epoxy steroids of the pregnene series; (B) 2l-bromo or chloro-9a-halo-1l 3-hydroxy or ll-keto steroids of the pregnene series; (C) 21-quaternary ammonium-9a-halo-llfi-hydroxy or ll-keto steroids of the pregnene series; and (D) 2l-nitrone-9a-halo-1lfihydroxy or keto steroids of the pregnene series.

For a clearer understanding of the foregoing general and following detailed description of the processes of this invention, reference is made to the following schematic analysis:

CHzOSOzR" rn (m/a 11+ 2 I wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded (those wherein the 1,2 and 6,7-positions are saturated and the 4,5-position is double-bonded being preferred), and wherein R is hydrogen, R is hydroxy, or together R and R is oxo (keto) or ketalized keto (it being understood that when R and R is a ketal group, the double bond, if any, in the 4,5-position shifts to the 5,6-position), R and R as 0x0 being preferred; Z is hydrogen or preferably a-hydroxy; R" is an alkyl radical, particularly a lower alkyl such as methyl, ethyl,

hexyl, etc. and is preferably methyl; X is chloro or bromo; X is halo (i.e. iodo, bromo. chloro or fluoro, and preferably is chloro or fluoro); M is a metal, such as an alkali metal or an alkaline earth metal, the halogen salt of which is soluble in the solvent employed in the indicated reaction, and preferably is alkali metal, such as potassium or lithium; T is a tertiary amine; W is an aromatic radical; and Y is CHO, CH(OH) CH(OB) or wherein B is lower alkyl or benzyl and B is lower alkylene.

The preparation of compounds suitable as initial reactants in the process of this invention is disclosed in our application, Serial No. 521,915, filed July 13, 1955. These compounds include the 21-alkane-sulfonyl, particularly the 2l-(lower alkane) sulfonyl, as exemplified by ethanesulfonyl, propanesulfonyl, hexanesulfonyl and especially methanesulfonyl, derivatives of the following: A pregene-9fl,llfi-oxido-Z1-ol-3,20-dione; A -pregnene- 9,8,1lfl-oxido-17a,21-diol-3,20-dione; A -pregnadiene-9 3- 11 3 oxido-21-ol3,20-dione; A -pregnadiene-9fl,11floxido 17a,21-diol-3,20-dione; A -pregnadiene-9/L11floxido21-o1-3,20-dione; and A -pregnadiene-9fi,11,8-oxido-l7a,21-diol-3,20-dione. As disclosed in said application, these starting materials are prepared by reacting the corresponding 21-free ol steroid with an alkanesulfonyl halide under substantially anhydrous conditions.

These starting materials, compounds A, are the reacted with a metal chloride or bromide (MX), wherein MX is as above-defined. Particularly preferred metal halides are lithium chloride and lithium bromide. Other utilizable salts include beryllium chloride, calcium chloride, potassium bromide, calcium bromide and barium bromide. The reaction is preferably carried out at elevated temperature in a substantially anhydrous organic solvent wherein the metal halide is soluble. Such solvents include the lower alkanolic acids (particularly glacial acetic acid), ketones (particularly acetone) and lower allkanols. If the reaction is conducted in a neutral solvent such as acetone, the product formed is the corresponding 9,8,1113- epoxy-Zl-halide, compounds B (wherein the halide corresponds to the halogen of the metal halide reactant). If, however, an acidic solvent, such as glacial acetic acid, is used, then the epoxy ring is opened to directly yield the corresponding 1lfi-hydroxy-9,B,21-dihalide derivative,

compounds C, wherein the halo substituents correspond to the halogen of the metal halide reactant.

Compunds B are then reacted with a hydrogen halide (i.e. hydrofluoric, hydrochloric, hydrobromic, or hydroiodic acid) in a suitable solvent (e,g. chloroform), as disclosed in the application of Josef Fried, Serial No. 417,489, filed March 10, 1954. By this reaction, compounds C are formed having a 9ct-halo and llp-hydroxy radical and a 21-halo substituent corresponding to the substituent in compound B. The llfi-hydroxy group present in compounds C or the corresponding llfi-hydroxy group present in compounds D, E, and F, can, if desired, be oxidized to the corresponding keto group in the usual manner, as by treating the steroid with chromic acid in glacial acetic acid. Thus, the first class of novel intermediates of this invention may be represented by the general formula wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded (preferably the 1,2 and 6,7 positions are saturated and the 4,5-position is double-bonded), R" is hydrogen, R'" is B-hydroxy, or together R and R is keto, and R, R, X, X, and Z are as hereinbefore defined.

These compounds may also be prepared directly from the corresponding 21-alkanesulfonyloxy derivatives (steroids which are disclosed in our application, Serial No. 516,333, filed June 17, 1955) by reaction thereof with the metal halide, MX', wherein MX is as hereinbefore defined, under substantially anhydrous conditions, preferably at an elevated temperature in the presence of an organic solvent for the metal halide (e.g. glacial acetic acid or acetone).

Compounds C can then be converted to compounds D by reacting with a tertiary base (T) at an elevated temperature. Among the tertiary bases which can be mentioned as examples are the aromatic amines (e.g. pyridine, picolines, lutidines, and quinolines). The resulting quaternary ammonium salts may be represented by the following general formula In the next step of the process of this invention, the quaternary ammonium halide, compounds D, are reacted with a nitroso compound, preferably an aromatic nitroso compound (WN=O), such as nitroso benzene and pnitroso-dimethylaniline, in the presence of a basic reagent such as potassium bicarbonate. By this procedure, a 21- nitrone, compound E, is formed. These nitrones are exemplified by those of the following general formula wherein one of the positions 1,2; 4,5; and 6,7 is doublebonded (preferably the 4,5 position is double-bonded) and the 1,2 and 6,7 positions are saturated, R, R, R, R", Z, and X are as hereinbefore-defined, and W is an aromatic radical such as phenyl and p-dimethylamino phenyl.

To convert the ZI-nitrones, compounds E, to an acetal derivative of a 2l-aldehyde, the former is then reacted, according to the process of this invention, under anhydrous conditions in an acidic medium with either a monohydric alcohol of the formula EOH or a dihydric alcohol of the formula B(OH) wherein B and B are as above-defined, preferably with an alcohol of the formula BOH, wherein B is a lower alkyl (e.g. methyl, ethyl, n-propyl, or n-butyl) or benzyl radical. The reaction is preferably carried out by dissolving or suspending the starting material in an anhydrous organic-solvent, such as chloroform, acetone, dioxane, etc., and treating the solution with a mineral acid such as hydrogen chloride or a strong organic acid, such as trichloroacetic acid or p-toluene sulfonic acid, dissolved in the alcohol reactant. The ratio of alcohol to steroid for the reaction is preferably at least two equivalents of alcohol (i.e. two moles of an alcohol BOH or one mole of an alcohol B(OH) per mole of steroid. If the alcohol reactant is a lower alcohol, the nitrone can be suspended directly in the mineral acid-alcohol solution, thereby eliminating the organic solvent. The reaction proceeds readily at room temperature, but may be conducted at any temperature in the range of about 25 C. to about C.

The acetal derivative formed by this step of the process of this invention may then be converted to the corresponding free aldehyde by reacting the acetal with an aqueous mineral acid, such as hydrochloric acid or perchloric acid, in mixture with an organic solvent, such as acetic acid, dioxane, acetone, etc., preferably at room temperature.

The free aldehydes can also be prepared directly from the nitrones by reacting the latter with the aforementioned mineral acids or strong organic acids, in an inert organic solvent such as acetone, acetic acid, dioxane, etc., preferably at room temperature. These free aldehydes can then in turn be converted to either the acetalized derivatives by treatment with an alcohol, such as those of the formula BOH and B(OH) under acidic conditions, or the diesterified derivatives by treatment, in an organic base (e.g. pyridine), with an anhydride, such as those of the formula wherein B is as hereinbefore-defined, as exemplified by acetic anhydride.

A modification of the process of this invention consists of the direct oxidation of an acetal derivative of a 2l-aldo steroid having an llfl-hydroxy group to the corresponding acetal derivative having an ll-keto group. Thus, to form a 2l-aldo steroid having an ll-keto group, instead of starting with the corresponding steroid having an 11- keto group and converting this ll-keto steroid to acetal derivative and thence to the free aldehyde, the llfl-hydroxy derivative (R is hydrogen, R' is S-hydroxy) is chosen as the initial reactant, and this reactant is converted to the 21-acetal derivative. The acetal derivative is then reacted with a customary oxidizing agent, such as chromic oxide in a basic medium such as pyridine, to oxidize the llfi-hydroxy group to keto, and the 11-keto Zl-acetal derivative thus formed is then converted to the free 2 l-aldehyde.

For the purpose of illustrating one process of this invention, reference is made to the following schematic analysis employing A*-pregnane-9,6,115-oxids-17u,21-diol-3, ZO-dione 21-mesylate as starting material:

H+ aqueous (acetone) The acetal derivatives and the free aldehydes which represent the final products of the processes of this invention are active materials which possess glucocorticoid as well as mineralocorticoid activity. Thus, they can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, and desoxycorticosterone in the treatment of Addisons disease or adrenal insufficiencies. The dosage for such administration is of course dependent on the relative activity; thus, where the acetal derivative, for example, has activity of the same order as hydrocortisone, for example, the dosage is of the same order. v

The following examples are illustrative of the invention (all temperatures being in centigrade):

A solution of mg. of M-pregnene-QBJlfl-oxidol7a,2l-diol-3,20-dione Zl-mesylate (I) and 300 mg. of anhydrous lithium bromide in 5 ml. of acetone is refluxed for /2 hour. After removal of the acetone in vacuo the residue is taken up in Water and chloroform and the resulting chloroform extract washed with dilute sodium bicarbonate solution and water. -After drying over sodium sulfate the chloroform solution is evaporated to dryness in vacuo and the resulting crystalline residue recrystallized from acetone. Pure 21-bromo-A -pregnene-9{3,llfi-oxido- 17a-ol-3,20-dione has the following properties: M.P. 193 (dec.); [cc] +18 (c, 0.71 in CHCl Analysis.-Calcd. for C I-1 0 131 (423.33); C, 59.58; H, 6.42. Found: C, 59.56; H, 6.74.

EXAMPLE 2 21-chl0r0-A -pregnene-9B,11/3-oxido-17a-0l-3,20- dione (III) A suspension of A -pregnene-9fl,l1,B-oxido-17a,2l-diol- 3,20-dione 21-mesylate (I) and 300 mg. of lithium chloride in 6 ml. of acetone is refluxed for 2 hours. After removal of the solvent in vacuo the residue is distributed between water and chloroform. The chloroform solution is dried over sodium sulfate and concentrated'to dryness in vacuo. The crystalline residue consisting of 21-chloro- A -pregnene-9fl,11fi-oxido-17oc-o1-3,20-dione after recrystallization from acetone has the following properties, M.P. about 235236 (dec.); [a] -l28 (c, 0.39 in dioxane);

Mm, 243 mp. --15,200); Ami? 2.87p (OH); 5.78;: (20- keto); 6.08 6.14;; (A -3-ketone) Analysis.-Calcd. for C21H27O4C]. (379): C, 66.58; H, 7.18. Found: c, 67.01; H, 7.09.

The epoxides formed by the procedures of Examples 1 and 2 can then be converted to the corresponding 9a-halo- 11 ,B-hydroxy derivatives as illustrated in the following two examples:

A -pregnene-11B,17a-diol-3,20-dione (IV) is formed.

EXAMPLE 4 21 -chlro-9a-fluor0-A -pregnene-1 15,1 7a-di0l-3,20- dione (VIII) Anhydrous hydrogen fluoride is added to a solution of 66 mg. of 21-chloro-A -pregnene-9fi,11fi-oxide-17a-ol-3, ZO-dione in 9.5 ml. of chloroform and 0.5 ml. of alcohol (contained in a polyethylene vessel provided with a copper inlet tube). During the addition, the solution is maintained in an ice bath and agitated by magnetic stirring, until the solution assumes a prominent red color. The inlet tube is then replaced by a polyethylene cap, and the reaction allowed to proceed with stirring for 1.5 hours at 0. Concentrated aqueous sodium bicarbonate solution is then added until the mixture is slightly alkaline, and the two layers are separated. The now light-yellow chloroform solution is washed with water; and after drying over sodium sulfate, it, is evaporated to dryness in vacuo. The residue is then taken up in hot ethyl acetate, the resulting suspension filtered, and the filtrate, on cooling, deposits a crystalline precipitate. This material is essentially pure 21-chloro-9o-fluoro-A -pregnene-115,1711:- diol-3,20-dione which is recrystallized from ethyl acetate to give a pure product having the properties described in Example 7. i

If hydrochloric acid is substituted for the hydrofluoric acid in the procedure of Example 4, 9a,21-dichloro-A pregnene-l1B,17u-diol-3,20-dione (IX) is formed.

Similarly if hydrobromic or hydroiodic acid is substituted for the hydrochloric or hydrofluoric acid in the procedures of Examples 3 and 4, the corresponding 90:- bromo and 9a-iodo derivatives are formed.

9:,2l-dichloro-M-pregnene-l1 8,170 diol 3,20 dione (IX) can also be prepared directly from A -pregnene-9/3, 1lfl-oxido-17a,21-diol-3,20-dione 21 mesylate (I) as disclosed in the following example:

EXAMPLE 5 9a,21-dichl0r0-A -pregnene-11BJ 7a-diQl-3,20-di0n c (IX) 289 3.04 (OH) 5.83 (-keto) 6.0 (A .-3-l'etone) Analysis.Calcd. for C H O Cl (414.34): C, 60.73; H, 6.79; Cl, 17.07. Found: C, 61.01; H, 6.89; CI, 17.55. The 9a-halo, llfi-hydroxy steroids having a '2l-bromo or chloro substituent can also be prepared from the'cor responding 21-alkanesulfonyloxy derivatives as illustrated by the following examples:

EXAMPLE 6 9a-flu0r0-21 -bromo-A -pregnene -1 1 3,1 7a-di0l-3,20.-

' dione (I V) A solution of 100 mg. of 9a-fiuorohydrocortisone 21- mesylate and 160 mg. of lithium bromide'in 3 ml. of glacial acetic acid is refluxed for /2 hour. The mixture is concentrated in vacuo to small volume and the residue distributed between water and ethyl acetate. The ethyl acetate layer is washed with dilute sodium bicarbonate solution and with water, and dried over sodium sulfate. Evaporation of the solvent in vacuo leaves the 21-bromo compound as a crystalline residue, which after recrystallization from 95% ethanol has the following properties, IVLP. about 252 (dec.); [a] +140 (c, 0.43 in dioxane);

Analysis.-Calcd. for C H O FBr (443.35): C, 56.89;

H, 6.37; Br, 18.26. Found: C, 56.85; H, 6.37; Br, 18.10.

EXAMPLE 7 A solution of 9a-fluorohydrocortisone 21-1nesylate and 200 mg. of anhydrous lithium chloride in 3 ml. of glacial acetic acid are heated under reflux for one hour. The solution is concentrated in vacuo and the residue distributed between water and ethyl acetate. The ethyl acetate layer is washed with dilute bicarbonate solution and with water and dried over sodium sulfate. Evaporation of the solvent in vacuo leaves the 21-chloro compound as a crystalline residue (about mg), which after recrystallization from ethanol melts at about 267269 (dec.); [ah -H53 (c, 0.30 in dioxane);

A213; 238 mp (6.=V17,7OO); REL-if" 2.88% 3.031.; (OH), 5.83;; (ZO-keto), 6.08 (A -3-ketone) Analysis.--Calcd. for C H O FCl (398.89): C, 63.23; H, 7.08; Cl, 8.89. Found: C, 63.25; H, 7.34; Cl, 8.44.

The reactions of Examples 6 and 7 can also be carried out with acetone as the solvent.

Similarly, by substituting either 9a-chlorohydrocortisone 21-mesylate or 9a-brornohydrocortisone 2l-mesylate for the 9tX-flUOI'OhydTGCOI'tlSOI1e 2l-mesylate in the procedures of Examples 6 and 7, the corresponding 2l-bromo and 2l-chloro derivatives are obtained, respectively.

The 9a-halo-11,8-hydroxy-21-bro-mo or chloro steroids produced by the procedures of Examples 3 through 7 can be oxidized to the corresponding 9oc-l1fllO-1l-kC'EO-21- brorno or chloro derivatives as illustrated by the following example:

2.88 3.08[.L (OH), 5.86u

To a solution of mg. of 9a-fiuoro-21-chloro-A pregnene-l1 3,17a-diol-3,20-dione in 5 ml. of glacial acetic acid is added a solution of 40 mg. of chromic acid in 4 ml. of acetic acid. A half-hour later, 0.05 ml. of methanol is added, and the resulting mixture is concentrated in vacuo. The residue is distributed between chloroform and water, and the resulting chloroform extract is washed with water, sodium bicarbonate solution and again with water. After drying over sodium sulfate and evaporation of the solvent in vacuo, the residue is crystallized from 95 ethanol to give pure 9a-fluoro-2l-chloro-A -pregnene-17aol-3 ,11,20-trione.

Similarly, by substituting 9a-fluoro-21-bromo-A -pregnene-l1/3,17u-diol-3,20-dione (IV), 9u-chloro-21-bromo- A -pregnene-1lfl,l7a-diol-3.20-dione (V), or 90,21-dichloro-M-pregnene-llfiJ7a-diol-3,20-dione (IX) for the 9a-fiuoro-2l-chloro-M-pregnene-l15,17 -'diol --3,20 dione (VIII) in the procedure of Example 8, 9a-fluoro-2lbromo-M-pregnene-17a-ol-3,11,20-trione (VI), 9a-chloro- 21-bromo-A -pregnene-l7a-ol-3,l1,20-trione (VII), and 9a,2l-dichloro-n -pregnene-1711-01-3,11,20-trione (XI) are obtained, respectively. 7

The 9a-halo-llB-hydroxy (or 1l-keto)-21-bromo or chloro steroids formed in the procedures of Examples 3 through 8 can be converted to their 21-pyridinium derivatives as illustrated in the following example:

EXAMPLE 9 A solution of 156mg. of 9a-fluoro-21-chloro-A -pregnene-l1fl,l7a-diol-3,20-dione in 3 ml. of dry pyridine is heated on the steam bath for 30 minutes and after cooling 5 ml. of acetone is added. Cooling produced a crop of crystals (about 123 mg.), M.P. 319-321" (dec.), which represent the Zl-pyridinium chloride. Fromthe mother liquors about 32 mg. of starting material M.P. 263 (dec.) is recovered.

p The 2l-pyridinium halides can be prepared directly from the 21-alkanesulfonyloxy derivatives as illustrated by the following two examples:

EXAMPLE A solution of 500 mg. of 9a-fluorohydrocortisone 2lmesylate in 5 ml. of anhydrous pyridine is heated on the steam bath for 30 minutes. To this solution which contained 9a-fluoro-A -pregnene llfl,l7a-diol3,20-dione-2lpyridinium rnesylate is added after cooling 3 ml. of 2% methanolic hydrogen chloride and shortly thereafter 20 ml. of acetone. Crystallization-of 9a-fluoro-A -pregnene- 11}3.l7u-diol-3,20-dione 21-pyridinium chloride ensues rapidly and is complete after several hours in the refrigerator.

The resulting crystals are filtered off and washed with acetone. Recrystallization from methanol furnishes the pure Zl-pyridinium chloride, M.P. about 320-321 (dec.); [a] +200 (c, 0.22 in methanol);

nia. 239 m, (e=19,600)

Analysis.Calcd. for C H O NC1F (477.99): C, 65.33; H, 6.96; CI, 7.42. Found: C, 65.48; H, 6.82; Cl, 7.37.

Following the procedure of Example 9, by substituting 9a-fluoro-2l-bromo-M-pregnene-l118,17a-dio1-3,20 dione (IV), 9a-chloro-21-bromo-A -pregnene-1 1fl,l7u-diol-3,20 dione (V), 9a-fiuoro-2l-brom0-A -pregnene-1705-01-3,1l, 20-trione (VII), 901,21-dichloro-A -pregnene-11fi,17a-diol- 3,20-dione (IX), 9a-fluoro-2l-chloro-N-pregnene-l7a-ol- 3,11,20-trione (X), and 9a,2l-dichloro-M-pregnene-17a- 3,11,20-trione (XI) for the 9a-fiuoro-2l-chloro-M-pregnene-l1B,17a-diol-3,20-dione, there is obtained compounds XII, XIII, XIV, XV, XVII, XVIII, and XIX, respectively.

' Compounds XII through XIX can also be prepared directly from the corresponding 9a-halohydrocortisone or 9a-halocortisone by reaction thereof with p-toluenesulfonyl chloride or bromide in anhydrous pyridine at an elevated temperature as illustrated by the following example:

EXAMPLE 11 Qua-chloro-M-pregnene-IIBJ7a-diol-3,20-diane ZI-pyridinium chloride (XVII) and 9:1,21-dichloro-A -pregnene- 115,1 7a-di0l-3,20-di0ne (IX) from 9a-chl0r0hydr0 cortisone A solution of 500 mg. of 9a-chlorohydrocortisone and washed with acetone. It represents the desired 2l-pyridinium chloride, M.P. about 287 (dec.) and is used without further purification in the nitrone formation reaction. Concentration of the mother liquor afford an additional crop of this substance and then two crops of a lower melting substance, M.P. about 235237, which is recrystallized from alcohol. The latter substance represents 9a,2l-dichloro-A -pregnene-1118,170 diol 3,20 dione; [a] -[-178 (c, 0.28 in absolute alcohol);

x515, 241 mu (e=16,000); A513? 2.87 (11-OH)3.01

(17OH), 5.83; (20-keto), 6.08, (3-keto) Analysis.--Calcd. for C H O Cl (415.34): C, 60.72; H, 6.79; Cl, 17.08. Found: C, 60.79; H, 6.70; Cl, 16.66.

If p-toluenesulfonyl bromide is substituted for p-toluenesulfonyl chloride in Example 11, the resulting mixture will consist of the 2l-pyridinium bromide (XIII) and the 21-bromide (V). Furthermore, upon the substitution of 90achlorocortisone for the 9oc-Cl'llOl'O-l'lYdIOCOItlSOIlC, either a mixture of 9a-chloro-A -pregnene-17u-ol,3,11,20-trione 2lpyridinium chloride (XIX) and 9a,2l-dichloro-A -pregnene-17a-ol-3,11,20-trione (XI), or 9a-chlo1o A -pregnene-l7or-ol-3,11,20-trione 2l-pyridinium bromide (XV) and 9u-chloro-2l-bromo-M-pregnene-l7a-ol-3,11,20-trione (VII), depending on whether tosyl chloride or tosyl bromide is used, will be formed.

Since the tertiary base is eliminated in the next step of the process, the exact chemical composition of the base is of no importance, so that any other tertiary base may be substituted for pyridine in the processs of the above Examples 9, 10, and 11 to yield other quaternary ammonium salts. Examples of such bases include the lutidines, the

collidines, the tri(lower alkyl)amines (e.g. trimethylamine and triethylamine), N-alkylated piperidine, etc.

The formation of the nitrones in the next step of the process of this invention is illustrated by the following examples, using p-nitrosodimethyl aniline as a source of the nitroso reactant:

EXAMPLE 12 pregnene-I 1,8,1 7u-di0l-3,20-di0ne 21 -pyridinium chloline and shortly thereafter a solution of 55 mg. of potassium bicarbonate (0.55 millimole) in 0.7 ml, of water. The mixture is gently warmed on a steam bath and then allowed to remain in the refrigerator overnight. The resulting red crystals (about 170 ,mg.) are filtered off, washed with 1:1 methanol-water and the mother liquors concentrated in vacuo. An additional crop (about 47 mg.) is obtained in this manner. The nitrone is used in the preparation of the aldehyde without further purification. For analysis the unstable nitrone is recrystallized from methanol, M.P. about 226 (dec.);

kg}; 240 mu (e=25,000), 304 my (e=9,400) and 415 m (e=12,850)

Analysis.Calcd. for C29H3qO5N2F (512.61): C, 67.94; H, 7.28; N, 5.47. Found: C, 68.87; H, 7.36; N, 6.28.

EXAMPLE 13 9a-chl0ro-A -pregnene-1]}3,17a-di0l-3,20-dione 21 (p-di methyl-aminophenyl)-nitr0ne (XXI) from 9a-chl0r0- M-pregnene-I1,3,17a-di0l-3,20 dione 21 pyridinium chloride (XVII) To a warm suspension of mg. of 9a-chloro-A -pregnene-llfl,17a-diol-3,20-dione 2l-pyridinium chloride in 3.8 ml. of methanol and 2.4 ml. water is added 477mg. of p-nitrosodimethyl aniline. When the latter has dissolved a solution of 30 mg. of potassium bicarbonate in 0.38 ml.

of water is added and the mixture warmed on the steam bath until all the pyridinium salt has dissolved, and has been replaced by the red crystals of the nitrone. The re-.

action mixture is then cooled and allowed to remain in the refrigerator for one hour. The crystals are filtered and washed with 50% methanol-water and finally with Water. The yield of nitrone is about 104 mg, M.P about 206. The substance is used in the preparation or" the aldehyde without further purification.

In an analogous manner the pyridiniurn bromides (XII) and (XIII) can be converted to the 9ix-fluoro and 9achloro derivatives, respectively.

If 9u-fiuoro-A -pregnene-l7ot-ol-3,11,20-trione 21 pyridinium chloride (XVIII) or bromide (XIV) is substituted for the pyridinium chloride in Example'12, 9a-fluoro-A p-regnene-17a-ol-3,11,20-trione 21-(p-dimethylaminophenyl)-r.itrone (XXII) is formed. Similarly, if 9oc-Chl010- A -pregnene-17ot-ol-3,11-20-trione 21-pyridinium chloride (XIX) or bromide (XV) is substituted for the pyridinium chloride in Example 13, 9a-chloro-A -pregnene-1701-01-3, 11,20-trione 21 (p dimethylaminophenyl) nitrone (XXIII) is produced. Analogously, the quaternary ammonium salts of the corticosterone and dehydrocorticosterone derivatives are converted to the corresponding nitrones.

Although the above examples employ p-nitrosodimethyl aniline as the source of the nitroso radical, any other aromatic nitroso-containing compound (such as nitroso benzene) may be used instead, since in the next step of the process the nitroso group is replaced by an aldo or acetalized aldo substituent.

The nitrone is then converted either to the 21-acetalized aldo or the free 21-aldo as illustrated by the following examples:

EXAMPLE 14 9a fluora A pregnene 115,170: diol 3,20 dione- 21 a! hydrate (XXIV) from 90c fluoro A pregnene 11/1170: diol 3,2 dione 21 (p-dimethylaminophenyl) -nitr0ne (XX) To a suspension of 120 mg.'0f 9a-fiuoro-A -pregnene- 11}8,l7a-diol-3,20-d ione (2l-p-dimethylaminophenyl)-nitrone in 2 ml. of acetone is added at roomtemperature 1 ml. of 2 N aqueous hydrochloric acid. Gentle agitation causes the nitrone to dissolve rapidly to form a yellow solution. After centrifugation of some insoluble matter 4 ml. of water is added, which causes the aldehyde hydrate to crystallize in fine needles. After one hour at the crystals are separated from the mother liquors and washed thoroughly with water. The resulting crystals (about 81.5 mg), after recrystallization from acetone-water melt at about, 190491", L 1 26 (c, 0.48 in methanol);

mtg- 238 m (e=18,300); 70,331? 3.0-3.2p (OH), 5.86; (20- keto), 6.15 1 (4-ket0) Analysis.-Calcd. for C 'H O F-I-I O (396.44): C, 63.62; H, 7.37; F, 4.79. Found: C, 63.71; H, 7.18; F, 4.87.

90; fiuoro A pregnene 115,170: diol 3.20 dione- 21-01 hydrate possesses about /3 the activity of cortisone acetate in the rat liver glycogen assay and is about equal in activity to desoxycorticosterone in the sodium retention assay in the rat.

EXAMPLE 15 9a chloro A pregnene 116,170: diol 3,20- dione 21 al hydrate (XXV) from 90: chloro- A pregnene 1113,1704 diol 3,20 dione 21 (pdimethylaminophenyl)-nitr0ne (XXI) 9a chloro A pregnene 11 9,17): diol 3,20- dione 2l-(p-dimethylaminophenyl)-nitrone is converted Min. 24 11114 m... 5.85 (20-keto), 12, (3-keto) Analysis.-Calcd. for C H O CLH O (412.90): C, 61.08; H, 7.08; Cl, 8.59. Found: C, 61.43; H, 6.73; Cl, 8.66.

c chloro A pregnene 115,170; diol 3, 20- dione-2l-al hydrate shows about /a the activity, of cortisone acetate in the rat liverglycogen assay. It is about 3 times as active as desoxy corticosterone in the sodium retention assay in the rat.

If 9a-fiuoro-A -pregnener17a-ol-3,11,20-trione 21-(p! dimethylamino phenyl)-nitrone ()OGI) is substituted for the 90: fluoro A pregnene 115,170: diol 3,20- dione 21-(p-dimethylaminophenyl-)-nitrone of Example 14, or if 9u-chlor0-A -pregnene-1701-01-3,11,20-trione ;2'1- (p-dimethylaminophenyl)-nitrone (XXIII) is substituted for the 9e-chloro-11B-hydroxy derivative of Example 15, then 94! -fiuoro A pregnene 17a 01 3,11,20 trione-Zl-al hydrate (XXVI) and 9a-ch1oro-A -pregnene- 17 t-ol-3,11,20-trione-21-al hydrate (XXVII) are formed, respectively. Similarly, by substituting the 21-(p-dimethylaminophenyl)nitrone derivatives of 9oz-flll01'0 (or chloro) A pregnene 11B ol 3,20 dione, or of 9u-fluoro (or chloro)-A -pregnene-3,l1,20-trione, or of 9a-fiu0ro (or chloro)-A -pregnene-l l fi-o1-3,20-dione-18+ al for the nitrone employed in Example 14, 9a.-fiuoro (or chloro) A pregnene 01 3,20 dione.- 2l-al hydrate, and 9a.-fiuoro (or chloro)-A -pregnene- 11,B-ol-3,20-dione-18,21 diol ZL-hydrate, respectively, are produced.

The ZI-acetals can be produced directly from the nitrones as illustrated by the following Example:

EXAMPLE 16 2.92pm, 3.05-3.09 (OH),

90: fluoro A pregnene 115,170: diol 3,20 dione 21 al dimelhyl-acetal (XX VIII from 9st fluoro- A -pregene 11 8,17 diol 3,20 dione 12 (p-dimethylaminophenyl)-nitr0ne (XX) To a suspension of mg. of 9u-fluoro-A -pregnene- 1113,1711. diol 3,2" dione 2'1 (p -dimethy lam inophenyl')-nitrone in 2 m1. of acetone is added at room temperature 1 ml. of 2 N methanolic hydrogen chloride. The mixture is taken up. in.20 ml. of chloroform and 4 ml. of .water. After separation of the phases, the chloroform layer is extracted with dilute bicarbonate and water and after drying over sodium sulfate, is evaporated to dryness in vacuum. The residue represents the di-, methyl acetal of -9,u-fluoro-A -pregnene-11p,18diol-3, 20-dione-21-al.

Similarly, by substituting 9e-chloro-A =pregnene-115, 17m diol 3,20 dione 21 (p dimethylaminophenyD- nitrone (XXI), 9a fluoro A pregnene 17a 01, 3,1 1,20 trione 21 (p dirnethylaminophcnyl) -nitr0ne (XXII), or 90: chloro A pregnene 17a ol 3,11,

13 The invention may be variously otherwise embodied within the scope of the appended claims.

We claim: 1. A process for preparing a steroid of the general formula wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded and R is hydrogen, R is hydroxy and together R and R is selected from the group consisting of keto and ketalized keto, Z is selected from the group consisting of hydrogen and a-hydroxy, and X is selected from the group consisting of bromo and chloro, which comprises treating a steroid of the general formula CHgOSO R wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded, R"" is alkyl, and R, R and Z are as above-defined with a salt selected from the group consisting of light metal bromides and light metal chlorides under substantially anhydrous conditions in a new tral organic solvent for the salt, and recovering the resultant steroid.

14 2. A process for preparing a steroid of the general formula omosom wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded, R"" is alkyl, and R, R, and Z are as above-defined with a salt selected from the group consisting of light metal bromide and light metal chloride in an acid organic solvent for said salt.

References Cited in the file of this patent UNITED STATES PATENTS 2,268,084 Reichstein Dec. 30, 1941 2,664,428 Miescher et a] Dec. 29, 1953 2,665,274 Conbere Jan. 5, 1954 2,842,568 Fried et al. July 8, 1958 2,851,455 Fried et al. Sept. 9, 1958 2,903,449 Fried et al. Sept. 8, 1959 

1. A PROCESS FOR PREPARING A STEROID OF THE GENERAL FORMULA 